Project Summary We propose to develop and test a novel noninvasive neuromodulation technique integrating transcranial focused ultrasound (tFUS) with electrophysiological source imaging (ESI) to allow real-time evidence-based neuromodulation with spatio-temporal precision for brain research and managing brain conditions. Despite the recent developments and attention surrounding tFUS, relatively little is known about the mechanisms and optimal parameters of this stimulation technology. The addition of simultaneous functional neuroimaging, aimed at providing biomarkers to assess the effects of tFUS neuromodulation, could provide crucial information regarding the neural response to the applied stimulation in real-time. In order for tFUS to be further developed and transformed into a robust neuromodulation technology, an integrated ESI-guided tFUS system to allow for individualized and responsive stimulation is urgently needed. Our hypothesis is that the integrated dense array EEG and tFUS system will provide important neural data to quantify and optimize stimulation effects in real- time. We further propose to develop a novel acousto-modulated ESI technique to significantly improve the spatial precision allowing for quantifying brain activity induced by tFUS. This proposed integration promises to result in a high spatiotemporal resolution neuromodulation system capable of being applied in a closed-loop and subject-specific manner. To achieve the proposed goal, we will address the following specific aims. Aim 1A. We will develop an ESI-tFUS system and validate the proposed methods in a rat model with simultaneous extracellular recordings of neural spikes and LFP activities. ESI will be performed from the scalp potential distribution and head anatomy to be obtained by structure imaging, and used to assess and optimize tFUS parameters and stimulation strategy. Aim 1B. We will develop an acousto-modulated ESI-tFUS system and validate the proposed methods in a rat model with simultaneous extracellular recordings of neural spikes and LFP activities. tFUS-induced brain activity will be monitored and imaged using the high spatial resolution acousto-modulated ESI, and used to assess and optimize tFUS parameters and stimulation strategy. Aim 2. We will develop an ESI (including acousto-modulated ESI) guided tFUS system for human use with real-time imaging capability. We hypothesize that the ESI-guided tFUS will provide real-time quantitative neural measures to be used to directly adjust tFUS parameters and strategy, allowing for optimization of tFUS stimulation. We will conduct online experiments in motor and somatosensory paradigms to test the merits of the proposed ESI-guided tFUS neuromodulation. The successful completion of the proposed research promises to develop a transformative technique for noninvasive neuromodulation with high spatio-temporal precision, individualized for each subject and responsive to dynamic neural activity recorded from the brain.